Glycolytic enzymes are attractive anticancer targets. They also carry out numerous, nonglycolytic "moonlighting" functions in cells. In this study, we investigated the anticancer activity of the triazine small molecule, GAPDS, that targets the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDS showed greater toxicity against cancer cells compared to a known GAPDH enzyme inhibitor. GAPDS also selectively inhibited cell migration and invasion. Our analysis showed that GAPDS treatment reduced GAPDH levels in the cytoplasm, which would modulate the secondary, moonlighting functions of this enzyme. We then used GAPDS as a probe to demonstrate that a moonlighting function of GAPDH is tubulin regulation, which may explain its anti-invasive properties. We also observed that GAPDS has potent anticancer activity in vivo. Our study indicates that strategies to target the secondary functions of anticancer candidates may yield potent therapeutics and useful chemical probes.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.chembiol.2014.08.017 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Elongator is a microtubule polymerase selective for polyglutamylated tubulin.
EMBO J
January 2025
Cell Biology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
Elongator is a tRNA-modifying complex that regulates protein translation. Recently, a moonlighting function of Elongator has been identified in regulating the polarization of the microtubule cytoskeleton during asymmetric cell division. Elongator induces symmetry breaking of the anaphase midzone by selectively stabilizing microtubules on one side of the spindle, contributing to the downstream polarized segregation of cell-fate determinants, and therefore to cell fate determination.
View Article and Find Full Text PDFMitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?
Biochemistry
January 2025
Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462066, India.
The mitochondrial outer membrane (OMM) β-barrel proteins link the mitochondrion with the cytosol, endoplasmic reticulum, and other cellular membranes, establishing cellular homeostasis. Their active insertion and assembly in the outer mitochondrial membrane is achieved in an energy-independent yet highly effective manner by the Sorting and Assembly Machinery (SAM) of the OMM. The core SAM constituent is the 16-stranded transmembrane β-barrel Sam50.
View Article and Find Full Text PDFNucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function.
Nat Commun
January 2025
Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy.
View Article and Find Full Text PDFNight flight facilitates late breeding catch-up in a long-distance migratory seabird.
Sci Rep
December 2024
Department of Biology, University of Oxford, Mansfield Road, Oxford, OX1 3SZ, UK.
Long-distance migrants must optimise their timing of breeding to capitalise on resources at both breeding and over-wintering sites. In species with protracted breeding seasons, departing earlier on migration might be advantageous, but is constrained by the ongoing breeding attempt. Here we investigated how breeding timing affects migratory strategies in the Manx shearwater (Puffinus puffinus), a trans-hemispheric migratory seabird with large temporal variation in the onset of breeding.
View Article and Find Full Text PDFNon-canonical function of PHGDH promotes HCC metastasis by interacting with METTL3.
Cell Oncol (Dordr)
December 2024
Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Article Synopsis
- PHGDH, an important enzyme in serine production, is found to promote the spread of hepatocellular carcinoma (HCC) by interacting with METTL3, suggesting a new avenue for cancer treatment.
- The study utilized various methods including Western blot and immunofluorescence to show that PHGDH levels increase under anoikis, enhancing HCC cell metastasis and preventing METTL3 degradation.
- Results indicate that the connection between PHGDH and METTL3 upregulates genes related to cell migration, ultimately supporting HCC metastasis, warranting further investigation as a therapeutic target.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!